Catalytic hydrogenation processes

ABSTRACT

Catalysts of formula 
 
[Ru(L) m (L′) w XY]  (II) 
wherein X and Y represent simultaneously or independently a hydrogen or halogen atom, a hydroxy group, or an alkoxy, carboxyl or other anionic radical, m is 1 or 2, w is 1 when m is 1 and w is 0 when m is 2, L is a phosphino-amine or phosphino-imine bidentate ligand and L′ a diphosphine, are useful for the hydrogenation of substrates having a carbon-hetero atom double bond.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 10/380,483filed Sep. 3, 2003, which is the 371 filing of International ApplicationPCT/IB01/01657 filed Sep. 11, 2001, which claims the benefit ofInternational Application PCT/IB00/01303 filed Sep. 13, 2000 and U.S.provisional application 60/232,144 filed Sep. 13, 2000. The entirecontent of each prior application is expressly incorporated here byreference.

TECHNICAL FIELD

The present invention relates to the field of catalytic hydrogenationand, more particularly, to the use of metal complexes with P-N bidentateligands in hydrogenation processes for the reduction of compoundscontaining a carbon-heteroatom double bond.

PRIOR ART

Reduction of carbon-heteroatom double bond groups such as ketone,aldehyde or imine groups, is one of the fundamental reactions inchemistry, and is used in a large number of chemical processes.

Several different kinds of processes are known to achieve suchtransformation, and they can be classified in four main types accordingto the nature of the reducing system:

-   a) enzymatic processes, in which an enzyme is used to catalyze the    reduction-   b) hydride processes, in which a hydride metal salt such as LiAlH₄    is used-   c) hydrogen transfer processes, in which hydrogen-donors such as    secondary alcohols and in particular isopropanol (^(i)PrOH) are used-   d) hydrogenation processes, in which molecular hydrogen is used.

However, from a practical point of view, the industrial application ofthe first two methods is difficult since the use of enzymes is delicateand can limit the structure of the compound that can be reduced. On theother hand, hydride processes require the use of highly reactive,hazardous and expensive hydrides.

Both hydrogen transfer and hydrogenation processes need a catalyst orcatalytic system (e.g. a pre-catalyst) to activate the reducing agent,namely an alcohol or molecular hydrogen respectively.

Despite the fact that many catalysts for the reduction of acarbon-heteroatom double bond by hydrogen transfer are already known,hydrogen transfer processes are still of difficult application forindustrial purposes since they need very large volumes of solvents asreducing agents and high catalyst loadings.

From a practical point of view, hydrogenation processes are moreattractive as they use cheap hydrogen gas and can be run out in thepresence of a small quantity or even in the absence of solvent, incontrast to the hydrogen transfer processes, which need large volumes ofsolvent as reductant. However, the former process implies the activationof molecular hydrogen, which is more difficult to achieve than theactivation of an alcohol.

For a long time the development of useful catalysts for thehydrogenation of carbon-heteroatom double bonds has been an unachievedgoal in chemistry, and it was only recently that several new catalystsfor the hydrogenation of ketones have been developed.

The hydrogenation catalysts for simple ketones reported up to now havethe same general formula, always including a ruthenium atom coordinatedby a bidentate ligand and two monodentate phosphines or amines, or twobidentate ligands. The bidentate ligands are always a diphosphine (P—P)or a diamine (N—N), and the metal centre is always coordinated to twophosphorous atoms and two nitrogen atoms. Very efficient pre-catalystsare those of the formula [Ru(P—P)(N—N)Cl₂] (see R. Noyori et al., inAngew.Chem.Int.Ed., 2001, 40, 41; Morris et al. in Organometallics,2000, 19, 2655; or Takasago EP 0901997 and JP 11189600).

From the examples cited herein above, one can notice that the catalystsreported up to now exhibit little diversity of the ligand structure andcoordination spheres around the metal center. As a consequence of suchlittle diversity, the tuning of the activity and of the performance ofthe hydrogenation process is not easy. Additionally, these catalystsgenerally need the use of ligands such as BINAP or sophisticated chiraldiamines which require themselves a long, difficult and tedioussynthesis.

Therefore, there is a need for hydrogenation processes using catalystsor pre-catalysts with a greater diversity in the ligand structures andcoordination spheres around the metal center, and implying the use ofligands that are easily and readily obtained.

DESCRIPTION OF THE INVENTION

In order to overcome the problems aforementioned, the present inventionrelates to new processes for the reduction by hydrogenation of compoundscontaining a carbon-heteroatom double bond wherein metal complexes withP-N bidentate ligands are usefully used as catalysts or aspre-catalysts.

The invention concerns a process for the hydrogenation, using molecularhydrogen (H₂), of a C═O or C═N double bond of a substrate into thecorresponding hydrogenated compound, in the presence of a catalyst orpre-catalyst (hereinafter referred to as “complex” unless specifiedotherwise) and a base.

More particularly, typical substrates that can be reduced by the processof the invention are of formula

wherein W is an oxygen atom or a NR group, R being a hydrogen atom, ahydroxy radical, a C₁ to C₈ cyclic, linear or branched alkyl or alkenylgroup, possibly substituted, or an aromatic ring, possibly substituted;and R^(a) and R^(b) represent simultaneously or independently ahydrogen, an aromatic group possibly substituted, a cyclic, linear orbranched alkyl or alkenyl group, possibly substituted, or a heterocyclicgroup possibly substituted; or two of symbols R^(a), R^(b) and R, takentogether, form a ring, possibly substituted,and provide the corresponding hydrogenated compound of formula

wherein W, R^(a) and R^(b) are defined as in formula (I).

Possible substituents of R^(a), R^(b) and R are halogen atoms, OR^(c),NR^(c) ₂ or R^(c) groups, in which R^(c) is a hydrogen atom or a C₁ toC₁₀ cyclic, linear or branched alkyl or alkenyl group.

Since R^(a) and R^(b) may be different, it is hereby understood that thefinal product of formula (I′) may be chiral, thus possibly consisting ofa practically pure enantiomer or of a mixture of stereoisomers,depending on the nature of the catalyst used in the process.

Preferred substrates are the imines (W═NR), ketones or aldehydes (W═O)that will provide respectively an amine or alcohol, which are useful inthe pharmaceutical, agrochemical or perfumery industries as finalproduct or as an intermediate.

Particularly preferred substrates are the ketones or aldehydes that willprovide an alcohol which is useful in the perfumery industry, as finalproduct or as an intermediate. Also particularly preferred substratesare the imines that will provide an amine, particularly useful in thepharmaceutical or agrochemical industries, again as final product or asan intermediate.

The processes of the invention are characterized by the use of a complexof the general formula[Ru(L)_(m)(L′)_(w)XY]  (II)wherein X and Y represent, simultaneously or independently, a hydrogenor halogen atom, a hydroxy radical, or a C₁ to C₈ alkoxy or acyloxyradical;

-   m is 1 or 2, w is 1 when m is 1 and w is 0 when m is 2;-   L represents a bidentate N-P ligand of general formula    in which formula (III) the dotted line indicates a single or double    bond;-   n is an integer from 1 to 4; z is 0 or 1 when the carbon-nitrogen    bond with the dotted line represents a double, respectively single    bond;-   R¹ represents a hydrogen atom, a linear, branched or cyclic C₁ to    C₁₀ alkyl or alkenyl group, possibly substituted, a R*CO acyl group,    or a R*SO₂ group, R* representing a C₁ to C₈ alkyl or aryl group;-   R² and R³ represent, simultaneously or independently, a linear,    branched or cyclic C₁ to C₈ alkyl or alkenyl group, possibly    substituted, an aromatic ring, possibly substituted, or an OR^(2′)    or NR^(2′)R^(3′) group, R² and R³ being defined as R² and R³; or    said groups R² and R³ being possibly bonded together to form a    saturated or aromatic ring having 5 to 10 atoms and including the    phosphorous atom to which said R² and R³ groups are bonded;-   R⁴, R⁵, R⁶ and R⁷represent, simultaneously or independently, a    hydrogen atom, a linear, branched or cyclic C₁ to C₁₀ alkyl or    alkenyl group, possibly substituted, an aromatic ring, possibly    substituted, or an OR⁴ or NR^(4′) R^(5′) group, R^(4′) and R^(5′)    being defined as R⁴ and R⁵; or two distinct R⁴ and/or R⁵ groups    being possibly bonded together to form a C₅ to C₈ saturated or    aromatic ring including the carbon atoms to which each of said R⁴ or    R⁵ group is bonded; or R⁶ and R¹ may optionally be bonded together    to form a saturated or unsaturated heterocycle, possibly substituted    and possibly containing other heteroatoms, having 5 to 10 atoms and    including the carbon atom and the N atom of the bond indicated by    the dotted line; and-   L′ represents a bidentate P—P ligand of formula    wherein R² and R³ are defined as in formula (III), and Q represents    a linear or cyclic C₂-C₇ alkylene radical, possibly substituted, a    metallocenediyl or a C₆-C₂₂ arylene or biaryldiyl radical, possibly    substituted.

Possible substituents of R¹ to R⁷ and Q are C₁ to C₁₀ alkoxy orpolyalkyleneglycol groups, carboxylic esters, C₁ to C₆ alkyl groups, orC₅ to C₁₂ cycloalkyl or aromatic groups.

The ligands L and L′ may be chiral or achiral. Therefore, the inventionmay provide complexes of formula (II) useful in asymmetrichydrogenations.

In a preferred embodiment of formula (II), X and Y represent,simultaneously or independently, a hydrogen or chlorine atom, a hydroxyradical, a C₁ to C₆ alkoxy radical, such as a methoxy, ethoxy orisopropoxy radical, or a C₁ to C₆ acyloxy radical such as a CH₃COO orCH₃CH₂COO radical;

-   m is 1 or 2, w is 1 when m is 1 and w is 0 when m is 2;-   L represents a bidentate N—P ligand of general formula    in which n is an integer from 1 to 3;-   R¹ represents a hydrogen atom, a linear, branched or cyclic C₁ to C₆    alkyl or alkenyl group, possibly substituted;-   R² and R³represent, simultaneously or independently, a linear,    branched or cyclic C₂ to C₆ alkyl group, possibly substituted, an    aromatic ring, possibly substituted; or said groups R² and R³ being    possibly bonded together to form a saturated or aromatic ring having    5 to 6 atoms and including the phosphorous atom to which said R² and    R³ groups are bonded;-   R⁴, R⁵, R⁶ and R⁷ represent, simultaneously or independently, a    hydrogen atom, a linear or branched C₁ to C₄ alkyl group, possibly    substituted, or an aromatic ring possibly substituted; or two    distinct R⁴ and/or R⁵ groups being possibly bonded together to form    a C₅ to C₆ saturated or aromatic ring including the carbon atoms to    which each of said R⁴ or R⁵ group is bonded; or R⁶ and R¹ may    optionally be bonded together to form a saturated heterocycle,    possibly substituted and possibly containing other heteroatoms,    having 5 to 6 atoms and including the carbon atom and the N atom of    the bond indicated by the dotted line; and-   L′ represents a bidentate P—P ligand of formula (IV) wherein R² and    R³ are defined as in formula (III′), and Q represents a linear C₂-C₅    alkylene radical, possibly substituted, a ferrocenediyl or a    biphenyldiyl or binaphthyldiyl radical, possibly substituted.

Possible substituents of R¹ to R⁷ and Q are C₁ to C₅ alkoxy orpolyalkyleneglycol groups, carboxylic esters, C₁ to C₄ alkyl groups, orC₅ to C₁₀ cycloalkyl or aromatic groups.

In an alternative preferred embodiment of the complexes of formula (II),X and Y represent, simultaneously or independently, a hydrogen orchlorine atom, a hydroxy radical, a C₁ to C₆ alkoxy radical, such as amethoxy, ethoxy or isopropoxy radical, or a C₁ to C₆ acyloxy radicalsuch as a CH₃COO or CH₃CH₂COO radical;

-   m is 1 or 2, w is 1 when m is 1 and w is 0 when m is 2;-   L represents a bidentate N—P ligand of general formula    in which G represents a group of formula R⁶C═NR¹ or a C═N    function-containing heterocycle, possibly substituted and possibly    containing other heteroatoms, such as a 2-pyridyl, a 1-oxazolinyl, a    2-imidazolyl or a 2-isoquinolinyl group;-   R⁶ represents a hydrogen atom, a linear or branched C₁ to C₄ alkyl    group, possibly substituted, or an aromatic ring possibly    substituted;-   n, R¹, R², R³, R⁴, R⁵ are defined as in formula (III′); and-   L′ represents a bidentate P-P ligand of formula (IV) wherein R² and    R³ are defined as in formula (III′), and Q represents a linear C₂-C₅    alkylene radical, possibly substituted, a ferrocenediyl or a    biphenyldiyl or binaphthyldiyl radical, possibly substituted.

Possible substituents of R¹ to R⁶, Q and G are C₁ to C₅ alkoxy orpolyalkyleneglycol groups, carboxylic esters, C₁ to C₄ alkyl groups, orC₅ to C₁₀ cycloalkyl or aromatic groups.

Particularly advantageous when used in the processes of the inventionare the complexes of formula[Ru(L)₂XY]  (II′)wherein X and Y represent, simultaneously or independently, a hydrogenor chlorine atom, a methoxy, ethoxy or isopropoxy radical, or a CH₃COOor CH₃CH₂COO radical; and

-   L is a ligand of formula (V) or (V′)    wherein the dotted lines in formula (V′) indicate the presence of a    phenyl or a naphthyl group;-   b represents 1 or 2;-   G′ represents a R⁶C═NR¹ group or a C═N function-containing    heterocycle, possibly substituted and possibly containing other    heteroatoms, such as a 2-pyridyl, an 2-isoquinolinyl, an    1-oxazolinyl, or a 2-imidazolyl group;-   R¹ represents a hydrogen atom or a C₁ to C₄ linear or branched alkyl    group, possibly substituted;-   R² and R³ represent a linear, branched or cyclic C₂ to C₆ alkyl    group or an aromatic ring, possibly substituted; and-   R⁶ represents a hydrogen atom, a linear or branched C₁ to C₄ alkyl    group, possibly substituted, or an aromatic ring, possibly    substituted.

Possible substituents of R¹ to R³, R⁶ and G′ are C₁ to C₅ alkoxy orpolyalkyleneglycol groups, C₁ to C₄ alkyl groups, or C₅ to C₁₀cycloalkyl or aromatic groups.

In an alternative embodiment of the complexes of formula (II′), L is aligand of formula (VI) or (VI′)

wherein the dotted lines in formula (VI′) indicate the presence of aphenyl or a naphthyl group;

-   R¹, R², R³, and b are defined as in formula (V) or (V′); and-   R⁶ and R⁷ represent, simultaneously or independently, a hydrogen    atom, a linear or branched C₁ to C₄ alkyl group, possibly    substituted, or an aromatic ring possibly substituted; or R⁶ and R¹    may optionally be bonded together to form a saturated heterocycle,    possibly substituted and possibly containing other heteroatoms, such    as a 2-pyrrolidine, a 2-piperidine or a 2-morpholine heterocycle.

Possible substituents of R¹ to R³, R⁶ and R⁷ are C₁ to C₅ alkoxy orpolyalkyleneglycol groups, C₁ to C₄ alkyl groups, C₅ to C₁₀ cycloalkylor aromatic groups.

Moreover, in the processes of the invention, it is possible to use in aparticularly advantageous manner the complexes of formula[Ru(L)₁(L′)₁XY]  (II″)wherein X and Y represent, simultaneously or independently, a hydrogenor chlorine atom, a methoxy, ethoxy or isopropoxy radical, or a CH₃COOor CH₃CH₂COO radical;

-   L′ is a bidentate P—P ligand of formula (IV) wherein R² and R³ are    defined as in formula (V), and Q represents the butane-1,4-diyl    radical, possibly substituted, a ferrocenediyl or a binaphthyldiyl    radical, possibly substituted; and-   L is a ligand of formula (VI) or (VI′).

Possible substituents of Q are C₁ to C₅ alkoxy or polyalkyleneglycolgroups, C₁ to C₄ alkyl groups, or C₅ to C₁₀ cycloalkyl or aromaticgroups.

In an alternative preferred embodiment of the complexes of formula(II″), L is a ligand of formula (V) or (V′).

The complexes of formula (II′) or (II″) are, to the best of ourknowledge, new compounds and therefore are also part of the invention.

Many of the ligands described above are known in the art and, unlessspecified differently in the examples, they are obtained according tomethods described in the literature. The ligands that are new can beobtained by modifying known procedures according to the generalknowledge of a person skilled in the art. Some references are cited inthe examples.

The complexes used in the processes of the invention can be prepared insitu in the hydrogenation reaction medium, without isolation orpurification, just before their use. Alternatively, they can be isolatedbefore use. The experimental procedure for their synthesis issubstantially similar in both cases. Furthermore, they can also beprepared and stored in solution, the latter being stable for many days.

Said complexes can be prepared according to methods similar to thosedescribed in the literature, e.g. by Noyori et al. in JP 11189600, or inAngew. Chem. Int. Ed. 1998, 37, 1703-1707, or by Yang et al. inC.R.Acad.Sci., Ser.IIc: Chim. 1999, 2, 251, or yet by Quirmbach et al.in Tetrahedron, 2000, 56, 775

As previously mentioned, the complexes can be prepared in situ, in thehydrogenation medium, by several methods without isolation orpurification, just before their use. We have established that one of thepossible procedures to advantageously prepare in situ a complex offormula (II) consists in reacting an appropriate Ru complex of formula[Ru(“diene”)(“allyl”)₂]in which “diene” represents a cyclic or linear hydrocarbon containingtwo carbon-carbon double bonds, conjugated or not, such as for example1,5-cyclooctadiene (COD) or 1,3-butadiene, and “allyl” represents alinear or branched C₃ to C₈ hydrocarbon radical containing onecarbon-carbon double bond, such as for example the allyl (CH₂CHCH₂) ormethylallyl (CH₂CCH₃CH₂) group, with a non-coordinating acid such asHBF₄.Et₂O, preferably one equivalent in respect to the metal, thentreating the resulting solution with the desired amount of a ligand L,and if necessary of ligand L′, as defined previously, and finallytreating the thus obtained mixture with a base in the presence of aprimary or secondary alcohol.

Preferably the [Ru(diene)(allyl)₂] is [Ru(COD)(allyl)₂] or [Ru(COD)(methylallyl)₂].

Another procedure to advantageously prepare in situ a complex of formula(II) consists in reacting a ruthenium complex of formula[Ru(C₆H₆)(Cl)₂]₂ with a required amount of ligand L, and if necessary ofligand L′, as defined previously, and then treating the thus obtainedreaction mixture with a base, in the presence of an alcohol.

In any case, and independently of the procedure chosen to prepare thecomplex in situ, the base used is, preferably, the same base used in theprocess of the invention.

As previously mentioned, the complexes of formula (II), (II′) or (II″)are very useful for the reduction by hydrogenation of compoundscontaining a carbon-heteroatom double bond. A typical process impliesthe mixture of the substrate with a complex of formula (II), (II′) or(II″), in the presence of a base and optionally a solvent, and thentreating such a mixture with molecular hydrogen at a chosen pressure andtemperature.

The complexes used in the processes of the invention, an essentialparameter of the process, can be added to the reaction medium in a largerange of concentrations. As non-limiting examples, one can cite ascomplex concentration values ranging from 0.1 ppm to 50000 ppm, relativeto the amount of substrate, thus representing respectively asubstrate/complex (S/com) ratio of 10⁷ to 20. Preferably, the complexconcentration will be comprised between 0.1 and 5000 ppm, i.e. a S/comratio of 107 to 200 respectively. More preferably, there will be usedconcentrations in the range of 0.5 to 1000 ppm, corresponding to a S/comratio of 2×10⁶ to 1000 respectively. It goes without saying that theoptimum concentration of complex will depend on the nature of the latterand on the pressure of H₂ used during the process.

As mentioned previously the process of the invention is performed in thepresence of a base.

Said base can be the substrate itself, if the latter is basic, or anyconventional base. One can cite, as non-limiting examples, organicnon-coordinating bases such as DBU, an alkaline or alkaline-earth metalcarbonate, a carboxylate salt such as sodium or potassium acetate, or analcoholate or hydroxide salt. Preferred bases are the alcoholate orhydroxide salts selected from the group consisting of the compounds offormula (R⁸O)₂M′ or R⁸OM″, wherein M′ is an alkaline-earth metal, M″ isan alkaline metal and R⁸ stands for hydrogen or a C₁ to C₆ linear orbranched alkyl radical.

Useful quantities of base, added to the reaction mixture, may becomprised in a relatively large range. One can cite, as non-limitingexamples, ranges comprised between 0.5 to 90000 molar equivalents,relative to the complex (e.g. base/complex=0.5 to 90000), preferably 5to 10000, and even more preferably between 10 and 5000 molarequivalents. However, it should be noted that, depending on thesubstrate and the complex structure, it is also possible to add a smallamount of base (e.g. base/complex=1 to 5) to achieve high hydrogenationyields.

The hydrogenation reaction can be carried out in the presence or absenceof a solvent. When a solvent is required or used for practical reasons,then any solvent current in hydrogenation reactions can be used for thepurposes of the invention. Non-limiting examples include aromaticsolvents such as benzene, toluene or xylene, hydrocarbon solvents suchas hexane or cyclohexane, ethers such as tetrahydrofuran, or yet primaryor secondary alcohols, or mixtures thereof. A person skilled in the artis well able to select the solvent most convenient in each case tooptimize the hydrogenation reaction, however primary or secondaryalcohols such as ethanol or isopropanol are the preferred solvents.

In the hydrogenation processes of the invention, the reaction can becarried out at a H₂ pressure comprised between 10⁵ Pa and 80×10⁵ Pa (1to 80 bars). Again, a person skilled in the art is well able to adjustthe pressure as a function of the catalyst load and of the dilution ofthe substrate in the solvent. As examples, one can cite typicalpressures of 1 to 40×10⁵ Pa (1 to 40 bar).

The temperature at which the hydrogenation can be carried out iscomprised between 0° C. and 100° C., more preferably in the range ofbetween 20° C. and 40° C. Of course, a person skilled in the art is alsoable to select the preferred temperature as a function of the meltingand boiling point of the starting and final products or of the solventif present.

Additionally, we surprisingly discovered that in some cases it ispossible to successfully hydrogenate some substrates into thecorresponding alcohols in the presence of hydrido or diacetato complexesof formula (II′), without a base.

Therefore, the invention concerns also a process for the reduction of anaryl or diaryl ketone into the corresponding alcohol by hydrogenation inthe presence of a complex, said process being characterized in that saidcomplex is of formula:[Ru(L)₂XY]  (II′)wherein L is as ligand of formula (V), (V′), (VI) or (VI′); and

-   X represents a hydrogen atom and Y represents a hydrogen or chlorine    atom, a methoxy, ethoxy or isopropoxy radical, or a CH₃COO or    CH₃CH₂COO radical; or X and Y represent a hydrogen atom or a CH₃COO    or CH₃CH₂COO radical.

Said processes are typically performed by admixing the substrate with acomplex of formula (II′), as herein above defined, optionally inpresence a solvent, and then treating such a mixture with molecularhydrogen at a chosen pressure and temperature. The concentration of thecomplex relative to the substrate, the nature of the optional solvent,the H₂ pressure and the temperature of the process are as previouslydescribed.

The invention will now be described in further detail by way of thefollowing examples, wherein the temperatures are indicated in degreescentigrade and the abbreviations have the usual meaning in the art.

All the procedures described hereafter have been carried out under aninert atmosphere unless stated otherwise. Hydrogenations were carriedout in open glass tubes placed inside a stainless steel autoclave or inSchlenk flasks. H₂ gas (purity: 99.99% or more) was used as received.All substrates and solvents were distilled from appropriate dryingagents under Ar. NMR spectra were recorded on Bruker instruments (¹H at400.1 MHz, ¹³C at 100.6 MHz, and ³¹P at 121.4, 145.8 or 161.9 MHz) andnormally measured at 300 K. Chemical shifts are listed in ppm.

EXAMPLE 1 Preparation of Some Ru Complexes of the Formula (II)

TABLE 1 Structure of the ligands of formula (IV) or (VI) used for thesynthesis of the corresponding complexes structure name

(VI)-1

(VI)-2

(VI)-3

(IV)-1

(IV)-2

(IV)-3Ligand (VI)-1 is commercially available from FLUKA.Ligands (VI)-2 and (VI)-3 were obtained from the correspondingamino-acids according to the procedure described in K. Kashiwabara, et.al.; Bull. Chem. Soc. Jpn., 1981, 54, 725; S. Sakuraba, et. al.; Chem.Pharm. Bull., 1995, 43, 927; A. Saitoh, et. al.; Synlett., 1999, 4, 483;A. Saitoh, et. al.; J. Org. Chem., 2000, 65, 4227.Ligands (IV)-1, 2, 3 are commercially available from Aldrich ChemicalCompany

a) Preparation of the Complex [RuHCl((VI)-1)₂]

Isopropanol (5 ml) was added to a mixture of [RuCl₂(COD)]_(n) (300 mg,1.07 mmol of Ru), NaOH (200 mg, 5.0 mmol) and (VI)-1 (510 mg, 2.2 mmol)under a flow of argon, and the resulting suspension stirred for 6 hours,during which a bright yellow precipitate formed. Water (30 ml) was addedand the mixture was stirred for another hour. It was then filtered usinga schlenk sintered glass frit, washed with water (3×10 ml) and vacuumdried. Recrystallization from toluene/hexanes afforded a pure sample ofthe complex. Yield=386 mg, 60%.

¹H NMR (C₆D₆): −19.83(t, ²J_(HP)=25.9 Hz, 1H, RuH); 2.18-4.54(m, 12H);6.90-7.38(m, 20H, Ph).

³¹P{¹H} NMR (C₆D₆): 77.8(s).

IR (Nujol): 1924 cm⁻¹ (vRuH), 3282, 3141 cm⁻¹ (vNH).

b) Alternative Preparation of the Complex [RuHCl((VI)-1)₂]

A solution of [RuHCl(Ph₃P)₃] (obtained as described by Schunn et al. inInorg.Synth., 1970, 131) (1002 mg, 1.00 mmol) and (VI)-1 (458 mg, 2.00mmol) in toluene (40 mL) was stirred and heated to 40° C. for 24 h andthen for another 2 h at 100° C. Then, about half of the solvent wasstripped off under vacuum from the yellow suspension, and the yellowprecipitate then directly collected by filtration at ambienttemperature. The filtrate was washed with pentanes and dried in vacuumto give 520 mg of [RuHCl(VI)-1)₂] (0.87 mmol, yield=87%).

¹H NMR (d₈-THF): −19.3 ppm (t, J=26.4 Hz, hydride);

¹H NMR (d₆-DMSO): −10.9 ppm (t, J=25.2 Hz, hydride);

³¹P{¹H} NMR (d₈-THF): 83.2 ppm (s);

³¹P{¹H} NMR (d₆-DMSO): 71.9 ppm (s).

c) Preparation of the Complex [RuCl₂((VI)-1)₂]

A 50 mg sample of [RuHCl((VI)-1)₂] was dissolved in methylene chloride(1.0 ml) and the resulting solution was allowed to stand at roomtemperature for 24 hours. A bright yellow precipitate was obtained uponaddition of diethyl ether (2 ml).

Yield=43 mg, 81%.

¹H NMR (CD₂Cl₂): 1.68-3.72 (m, 12H); 6.99-7.17 (m, 20H, Ph).

³¹P{¹H} NMR(CD₂Cl₂): 62.51 (s).

d) Alternative Preparation of the Complex [Ru(Cl)₂((VI)-1)₂]

Toluene (5 ml) was added to a mixture of [RuCl₂(COD)]_(n) (300 mg, 1.07mmol) and (VT)-1 (510 mg, 2.2 mmol) and the resulting suspensionrefluxed for 12 hours under argon, during which a bright yellowprecipitate formed. The mixture was cooled to room temperature and thesolids filtered, washed with toluene (3×5 ml), then ether (3×5 ml) andvacuum dried.

Yield=582 mg, 91%.

¹H NMR (CD₂Cl₂): 1.68-3.72 (m, 12H), 6.99-7.17 (m, 20H, Ph).

³¹P{¹H} NMR(CD₂Cl₂): 62.51.

e) Preparation of the Complex [RuHCl((VI)-2)₂]

This complex was prepared using a similar procedure to that described ina) or in b).

Yield=67% for method a).

¹H NMR (C₆D₆): −19.15(t, ²J_(HP)=25.4 Hz, 1H, RuH); 1.01-4.54(m, 16H);6.93-7.76(m, 20H, Ph).

³¹P {¹H} NMR (C₆D₆): 72.9(d), 72.4(d, ²J_(PP)=34.8 Hz).

f) Preparation of the Complex [RuCl₂((VI)-2)₂]

This complex was prepared using a similar procedure to that described ind) or in c). Yield=83% for method c.

¹H NMR (C₆D₆): 1.01-3.68(m, 16H); 6.87-62(m, 20H, Ph).

³¹P {¹H} NMR (C₆D₆): 57.5(s).

g) Preparation of the Complex [RuHCl((VI)-3)₂]

This complex was prepared using a similar procedure to that described ina) or in b) and resulted in a mixture of diastereomers. However, theisolated solid was effectively used as a catalyst precursor in theketone hydrogenation.

h) Preparation of the Complex [RuHCl((IV)-2)((VI)-1)]

A mixture of [RuHCl(IV-2)(PPh₃)] (300 mg, 0.29 mmol) (obtained accordingto Abdur-Rashid, K. et al. in Organometallics 2001, 20, 1047) and (VT)-1(70 mg, 0.30 mmol) in toluene (5 ml) was refluxed for 6 hours. Theresulting solution was concentrated to 1 ml and hexanes (10 ml) added,resulting in a bright yellow product. Yield=261 mg, 90%.

¹H NMR (C₆D₆): −17.75 ppm (dt, ²J_(HP)=20.6, 25.6 Hz, 1H, RuH),0.95-3.68 ppm (m, 6H), 6.22-8.83 ppm (m, 42H);

³¹P{¹H} (C₆D₆): 38.1 ppm (dd, ²J_(PP)=292, 32.5 Hz), 40.6 ppm (dd,²J_(PP)=292, 31.4 Hz), 67.5 ppm (dd, ²J_(PP)=32.5, 31.4 Hz)

IR (Nujol): 1986 cm⁻¹ (vRuH); 3329, 3259 cm⁻¹ (vNH).

i) Preparation of the Complex [RuHCl((IV)-2)((VI-2)]

This complex was prepared using a similar procedure to that described inh). Yield=272 mg, 93%.

¹H NMR (C₆D₆): −17.36 ppm (ddd, ²J_(HP)=21.7, 21.0, 20.1 Hz, 1H, RuH),0.85-3.00 ppm (m, 8 H), 6.22-6.88 ppm (m, 42 H);

³¹P {¹H} NMR (C₆D₆): 29.43 ppm (dd, 2J_(PP)=294, 31.2 Hz), 32.9 ppm (dd,²J_(PP)=294, 32.4 Hz), 63.4 ppm (dd, ²J_(PP)=31.2, 32.4 Hz).

IR (Nujol): 2006 cm⁻¹ (vRuH), 3320, 3250 cm⁻¹ (vNH).

j) Preparation of the Complex [RuHCl((IV)-1)((VI)-1)]

Synthesis of the precursor [RuHCl((IV)-1)(PPh₃)]: THF (20 mL) was addedto a mixture of (IV)-1 (2.0 g, 3.6 mmol) and RuHCl(PPh₃)₃ (3.3 g, 3.4mmol) and the resulting suspension was refluxed for 6 h under Ar. Thesolution was then evaporated to dryness under vacuum and the residue wasextracted with CH₂Cl₂ (2×15 ml) and filtered. The filtrate wasevaporated to dryness and ether (20 ml) was added to the residue. Thesuspension was stirred for one hour under N₂. The red-brown solids werefiltered, washed with ether (2×5 ml) and dried under vacuum. Yield=2.46g, 72%.

¹H NMR (C₆D₆): 6.9-8.0 ppm (m, 35 H, PC₆H₅), 4.56, 4.41, 3.94, 3.78 (br,each 2H, PC₅H₄), −19.52 (dt, ²J_(HP)=19.2, ²J_(HP)=30.6 Hz, RuH).

¹P{¹H} NMR (C₆D₆): 44.79 ppm (t, ²J_(PP)=131 Hz, PPh₃), 68.25 (br, 2PC₅H₄).

Synthesis of the title complex: A solution of (VT)-1 (240 mg, 1.03 mmol)in THF (5 ml) was added to [RuHCl((IV)-1)(PPh₃)] (950 mg, 1.0 mmol) andthe resulting solution stirred for two hours at 20° C. The solvent wasremoved under vacuum and the solids extracted with THF (3.0 ml) andfiltered. Hexane (20 ml) was added to the filtrate, yielding a paleyellow solid, which was filtered, washed with hexane (2×5 ml) and driedunder vacuum. Yield=623 mg, 67%.

This exists as two diastereomers in the ratio 2:1:

¹H NMR (C₆D₆): −17.91 ppm (dt, ²J_(HP)=20.2, 26.0 Hz, 1H, RuH of bothdiastereomers), 1.6-3.4 (several m, 6H dppea), 3.70, 3.75, 3.85, 3.90,4.09, 4.21, 4.31, 4.60, 5.30 (several m, 8H, PC₅H₄), 6.6-8.6 (several m,30H);

Diastereomer 1:

³¹P {¹H} NMR (C₆D₆): 58.4 ppm (dd of AMN, 2J_(PP)=31 (AM), 35 (AN) Hz),52.4 (dd of AMN, ²J_(PP)=286 (MN), 31 (AM) Hz), 47.7 (dd of AMN,²J_(PP)=286 (MN), 35 (AN) Hz).

Diastereomer 2:

³¹P {¹H} NMR (C₆D₆): 36.8 ppm (dd of AMN, 2J_(PP)=32 (AM), 30 (AN) Hz),33.0 (dd of AMN, ²J_(PP)=333 (MN), 32.3 (AM) Hz), 27.4 (dd of AMN,²J_(PP)=333 (MN), 30.5 (AN) Hz).

k) Preparation of the Complex RuHCl((IV)-3)((VI)-1)

Synthesis of the precursor [RuHCl((IV)-3)(PPh₃)_(n)], n=1, 2: THF (20ml) was added to a mixture of (IV)-3 (1.29 g, 2.6 mmol) and RuHCl(PPh₃)₃(2.36 g, 2.6 mmol) and the suspension refluxed for 6 h under Ar. Thesolvent was removed under vacuum and the solids extracted with THF (10ml) and filtered. The filtrate was evaporated to dryness and a mixtureof ether/hexane (1:5) (20 mL) was added. The suspension was stirredvigorously for 2 h. The red-brown solids were filtered off, washed withhexane and dried under vacuum. Yield=1.85 g, 69% (based on a 1:1 mixtureof isomers with n=1 and n=2).

Isomer with n=1.

¹H NMR (C₆D₆): −16.72 ppm (dt, ²J_(HP)=22, ²J_(HP)=31 Hz, RuH).

³¹P{¹H} NMR (C₆D₆): 81 ppm (br, P_(A) of AMX), 48 (br m, P_(M) of AMX,²J_(PP)=242 Hz), 35 (br m, P_(X) of AMX, ²J_(PP)=242).

Isomer with n=2.

¹H NMR (C₆D₆): −17.96 (tt, ²J_(HP)=13.4, ²J_(HP)=28.5 Hz, RuH).

³¹P{¹H} NMR (C₆D₆): 22.8 ppm (t, ²J_(PP)=40.2 Hz), 4.0 ppm (t,²J_(PP)=40.2 Hz).

Synthesis of the title complex: A solution of (VI)-1 (240 mg, 1.03 mmol)in THF (2.0 ml) was added to 900 mg of [RuHCl((IV)-3)(PPh₃)_(n)] (n=1, 2in 1:1 ratio) and the mixture was stirred for one hour at 20° C. underN₂. The mixture was filtered and hexanes (20 ml) were added to thefiltrate, precipitating a yellow-green solid which was filtered, washedwith hexane and dried under vacuum. Yield=582 mg, 76%.

This exists as two diastereomers in a ratio 1.5:1:

Diastereomer 1:

¹H NMR (C₆D₆): −18.1 ppm (dt, ²J_(HP)=19.8, 24.8 Hz, 1H, RuH);

³¹P {¹H} NMR (C₆D₆): 53.3 ppm (dd, ²J_(PP)=28, 280 Hz), 46.3 (dd,²J_(PP)=28, 31 Hz), 31.4 (dd, ²J_(PP)=280, 31 Hz).

Diastereomer 2:

¹H NMR (C₆D₆): −18.2 (dt, ²J_(HP)=19.8, 24.6 Hz, 1H, RuH);

³¹P {¹H} NMR (C₆D₆): 54.4 ppm (dd, ²J_(PP)=36, 283 Hz), 46.3 (dd,²J_(PP)=36, 35 Hz), 37.4 (dd, ²J_(PP)=283, 35 Hz).

l) Preparation of the Complex trans-[RuH₂((IV)-2)((VI)-1)]

Synthesis of precursor [K(18-crown-6)][RuH₃((IV)-2)(PPh₃)]: THF (2 ml)was added to a mixture of [RuHCl((IV)-2)(PPh₃)] (100 mg, 0.10 mmol), KH(20 mg, 0.5 mmol) and 18-crown-6 (26 mg, 0.10 mmol) under an atmosphereof H₂ gas. The mixture was stirred for 5 hours, filtered under anitrogen atmosphere and hexane (10 ml) added to the filtrate,precipitating a pale red-brown solid. Yield=95 mg, 74%.

¹H NMR (C₆D₆): −9.98 ppm (m, 1H, RuH), −9.36 ppm (m, 1H, RuH), −8.97 ppm(m, 1H, RuH), 3.24 ppm (s, 24H, CH₂), 6.24-8.76 ppm (m, 47H).

³¹P {¹H} NMR (C₆D₆): 59.1 ppm (m), 61.2 ppm (m), 64.7 ppm (m).

IR (Nujol): 1799, 1836 cm⁻¹ (vRuH).

Synthesis of the title complex: A mixture of[K(18-crown-6)][RuH₃((IV)-2)(PPh₃)] (100 mg, 77 mmol) and (VI)-1 (20 mg,86 mmol) in C₆D₆ (0.6 ml) was allowed to stand for 12 hours. The NMRspectrum shows a clean formation of the trans-dihydride complex.

¹H NMR (C₆D₆) Hydride region: −5.16 (m) ppm (m), −6.49 (m).

³¹P {¹H} NMR (C₆D₆): 67.4 (dd), ²J_(PP)=280, 33.4 Hz, 72.8 (dd),²J_(PP)=280, 38.6 Hz, 81.6 (dd), ²J_(PP)=38.6, 33.4 Hz

m) Preparation of the Complex [Ru(AcO)₂((VI)-1)₂]

A solution of Ru₂(AcO)₄ (13.1 mg, 0.03 mmol) (prepared according toLindsay et al. in J.Chem Soc.Dalton Trans. 1985, 2321) and (VI)-1 (27.5mg, 0.12 mmol) in CH₂Cl₂ (3 ml) was left for 24 h at ambienttemperature. Removal of the solvent in vacuum gave 38 mg of a brightyellow powder. Yield=93%.

³¹P{¹H} NMR (CD₂Cl₂): 50.2(s), 64.8 ppm (s).

EXAMPLE 2 Catalytic Hydrogenation of Ketones Using [RuXY((VI))₂] or[RuXY(VI)(IV)]

Under an atmosphere of hydrogen gas (1-3 atm) at room temperature,catalytic amounts of the complexes with a ligand of formula (VI)described in Example 1, together with 3-10 equivalents of KO^(i)Preffectively and readily catalyzed the hydrogenation of the neat ketoneto the corresponding alcohol. A typical catalytic run using[RuHCl((VI)-2)₂] and acetophenone as substrate is as follows:

Acetophenone (2.0 g) was added under a flow of hydrogen gas to a Schlenkflask containing [RuHCl((Vl)-2)₂] (5 mg) and KO^(i)Pr (5 mg). The flaskwas cooled to liquid nitrogen temperature, filled with H₂ gas, closedand allowed to gradually warm to room temperature. The mixture wasvigorously stirred for 12 hours. A ¹H NMR spectrum of the reactionmixture indicated complete conversion of the ketone to the alcohol.Under these conditions, the complexes reported in Table 2 resulted in100% conversion of the ketone to the corresponding alcohol (Table 2).TABLE 2 Hydrogenation of ketones using some [RuXY((VI))₂] or[RuXY(VI)(IV)] Test Sub. Complex Com/base Conv.  1 1 [RuHCl((VI)-1))₂]500/5000 100  1 1 [RuHCl((VI)-1))₂] 500/2500 100  2 1 [RuHCl((VI)-2)₂]500/2500 100  3 1 [RuHCl((VI)-3)₂] 400/2000 100  4 1 [RuCl₂((VI)-1))₂]400/2000 100  5 1 [RuCl₂((VI)-2)₂] 400/2000 100  6 1 [RuCl₂((VI)-3))₂]370/1900 100  7¹⁾ 1 [Ru(AcO)₂((VI)-1))₂] 100/500  100  8 2[RuCl₂((VI)-1))₂] 240/1200 100  9 2 [RuCl₂((VI)-2)₂] 240/1200 100 10 2[RuHCl((VI)-1))₂] 240/1200 100 11 2 [RuHCl((VI)-3))₂] 190/1200 100 12 3[RuCl₂((VI)-1))₂]* 2500/12500 100 13 3 [RuCl₂((VI)-2)₂]* 2500/12500 10014 3 [RuHCl((VI)-1))₂]* 2500/12500 100 15 3 [RuHCl((VI)-2)₂]* 2500/12500100 16 4 [RuCl₂((VI)-1)₂] 400/2000 100 17 4 [RuHCl((VI)-1)₂] 400/2000100 18 4 [RuHCl((VI)-2)₂] 1600/800  100 19 5 [RuHCl((VI)-1))₂] 400/2000100 20 1 [RuHCl((IV)-2)((VI)-1))] 240/1200 100^(2a)) 21 1[RuHCl((IV)-2)((VI)-2))] 240/1200 100^(2b)) 22 1[RuHCl((IV)-3)((VI)-1))] 240/1200 100 23 2 [RuHCl((IV)-2)((VI)-1))]300/1500 100 24 2 [RuHCl((IV)-2)((VI)-2))] 300/1500 100 25 3[RuHCl((IV)-1)((VI)-1))] 1750/8500  100 26 3 [RuHCl((IV)-3)((VI)-1))]1850/8500  100 27 4 [RuHCl((IV)-1)((VI)-1))] 550/2700 100 28 4[RuHCl((IV)-3)((VI)-1))] 580/2900 100 29 5 [RuHCl((IV)-1)((VI)-1))]500/2500 100 30 5 [RuHCl((IV)-3)((VI)-1))] 560/2800 100Sub.: Substrate: 1) = acetophenone, 2) = acetone, 3) =2,2-dimethyl-1-phenyl-propanone, 4) = 3,3-dimethyl-2-butanone, 5) =5-hexen-2-oneCom/base: molar ratio in ppm relative to the substrateConv. = conversion (in %, analysed by GC or NMR) of the ketone into thecorresponding alcohol (namely 1-phenyl-1-ethanol, isopropanol,2,2-dimethyl-1-phenyl-propanol, 3,3-dimethyl-2-butanol and 5-hexen-2-olrespectively) after 12 hours.Reaction conditions: H₂ gas (≈3.5 atm.), 20° C.*Hydrogenation performed in 1 g of C₆D₆ for 2.5 g of substrate¹⁾test performed at 40° C. and under H₂ gas (≈60 atm.), according thehydrogenation conditions described in example 3.^(2a))e.e. (S enantiomer) = 10%; 2b) e.e. (S enantiomer) = 40%

EXAMPLE 3 Catalytic Hydrogenation of2-ethyl-4-(2′,2′,3′-trimethyl-3′-cyclopenten-1′-yl)-2-buten-1-al using[RuXY((Vl)-1)₂] or [RuXY((VI)-1)((IV)-4)] prepared in situ Preparationin situ of a Ru/(VI)-1 solutionfrom [Ru(COD)(methylallyl)₂]

The entire procedure described herein below is carried out under inertatmosphere. 31.9 mg (0.1 mmol) of [Ru(COD)(methylallyl)₂] were dissolvedin 1 ml of CH₂Cl₂, and 0.10 mmol of HBF₄.Et₂O were added to thesolution. The solution thus obtained was stirred at room temperature for2 h, then 45.8 mg (0.2 mmol) of 2-diphenylphosphino ethylamine ((VI)-1)were added and the resulting mixture stirred for 2 h at roomtemperature.

Preparation in situ of a Ru/(VI)-1 solution from [Ru(C₆H₆)(Cl)₂]₂

A solution of [RuCl₂(C₆H₆)]₂ (25.0 mg, 0.05 mmol) and (VI)-1 (45.8 mg,0.20 mmol) in DMF (1.5 ml) was heated to 100° C. for 1 h. The solventwas stripped off in vacuum from the yellow solution, and the residue(yellow solid) taken up in CH₂Cl₂ (0.5 ml).

Hydrogenation:

1.0 μL of one of the above mentioned Ru/(VI)-1 solutions (0.0001 mmol,10 ppm with respect to the substrate) was added to a solution of thesubstrate (2.06 g, 10.0 mmol) and t-BuOK (100.8 mg, 0.90 mmol) in i-PrOH(2.20 ml), and the resulting solution exposed to H₂ (40 bar) at 60° withmagnetic stirring. The molar proportions correspond to 1 mol ofprecatalyst per 9000 mol of t-BuOK per 100,000 mol of substrate,{1:9000:100,000}, and the initial concentration of substrate in thei-PrOH was ˜2.4 M. Conversion to2-ethyl-4-(2′,2′,3′-trimethyl-3′-cyclopenten-1′-yl)-2-buten-1-ol wascomplete within 3 h.

Further runs were done on the same scale and under the same conditions,but with varying amounts of complex and t-BuOK, and essentially the sameresults were obtained except for the conversion at very low complexloading. The latter runs, at 1-5 ppm catalyst, relative to the amount ofsubstrate, can be pushed to completion by prolonging the reaction timeand/or raising the pressure and/or the temperature. A run with aRu/(VI)-1/(IV)-1 solution generated in situ has been also performed.TABLE 3 Hydrogenation of a sandranal using some [RuXY((VI))₂] or[RuXY(VI)(IV)] Conv./ Conv./ Test Complex Com/base time time 1[RuXY((VI)-1))₂]^(a))* 100/90000 100/3 h 2 [RuXY((VI)-1))₂]^(a))* 5/90000  94/3 h 100/20 h 3 [RuXY((VI)-1))₂]^(a))*  2/90000  34/3 h 88/20 h 4 [RuXY((VI)-1))₂]^(a))*  1/90000  28/3 h  79/20 h 5[RuCl₂((VI)-1)₂]*** 100/45000 100/1.5 h 6 [RuCl₂((VI)-1)₂]***  10/4500 50/3 h 100/20 h 7 [RuCl₂((VI)-1)₂]***  10/45000 100/1.5 h 8[RuXY((VI)-1)((IV-4)^(§)]^(a))**  10/45000 100/5 h 9[RuHCl((VI)-1))₂]^(b))  10/500  97/3 h Sandranal:2-ethyl-4-(2′,2′,3′-trimethyl-3′-cyclopenten-1′-yl)-2-buten-1-al ^(a))Xand Y represent a hydrogen atom or an alkoxy radical ^(b))Forcomparison, test performed with a complex pre-formed according to theprocedure of exemple 1b) Com/base: molar ratio in ppm relative to thesubstrate Conv./time = conversion (in %, analyzed by GC) of sandranalinto the corresponding alcohol at the indicated time in hours.

Ligand (IV)-4 is commercially available from FLUKA. *complex prepared insitu from [Ru(COD)(methylallyl)₂] **complex prepared in situ from[Ru(COD)(methylallyl)₂], according to the procedure herein-above, exceptthat it has been added 0.1 mmol of (VI)-1 and 0.1 mmol (IV)-4 ***complexprepared from [Ru(C₆H₅)(Cl)₂]₂.

EXAMPLE 4 Catalytic Hydrogenation of Some Ketones Using [RuCl₂((VI)-1)₂]Prepared in situ

Using a hydrogenation procedure similar to the one described in example3. The results are listed in table 4. TABLE 4 Hydrogenation of a someketones using [RuCl₂((VI)-1)₂] Test Sub Catalyst: Com/base Conv. 1 1[RuCl₂((VI)-1)₂]*  10/45000 63 2 1 [RuCl₂((VI)-1)₂]* 10/4500 15 3 2[RuCl₂((VI)-1)₂]*  10/45000 99 4 2 [RuCl₂((VI)-1)₂]* 10/4500 99Sub: Substrate: 1)3,3-dimethyl-5-(2′,2′,3′-trimethyl-3′-cyclopenten-1′-yl)-4-penten-2-one;2) = 4-(2′,6′,6′-trimethyl-1′-cyclohexen-1′-yl)-3-buten-2-oneCom/base: molar ratio in ppm relative to the substrateConv. = conversion (in %, analyzed by GC) of the ketone into thecorresponding alcohol after 3 hours.*complex prepared from the [Ru(C₆H₅)(Cl)₂]₂ as in example 3.

EXAMPLE 5 Catalytic Hydrogenation of Imines Using [RuXY((VI))₂] or[RuXY(VI)(IV)]

Under an atmosphere of hydrogen gas (1-3 atm) at room temperature,catalytic amounts of the complexes with a ligand of formula (VI)described in Example 1, together with 5-10 equivalents of KO^(i)Preffectively and readily catalyzed the hydrogenation of the imine to thecorresponding amine. A typical catalytic run using [RuHCl((VI)-1)₂] andN-(1-phenylethylidene)-benzenamine as substrate is as follows:

N-(1-phenylethylidene)-benzenamine (4.0 g) and C₆D₆ (1 g) were addedunder a flow of hydrogen gas to a Schlenk flask containing[RuHCl((VI)-1)₂] (105 mg) and KO^(i)Pr (10 mg). The flask was cooled toliquid nitrogen temperature, filled with H₂ gas, closed and allowed togradually warm to room temperature. The mixture was vigorously stirredfor 12 hours. A ¹H NMR spectrum of the reaction mixture indicatedcomplete conversion of the imine to the amine. Under these conditions,the complexes reported in Table 5 resulted in 100% conversion of theimine to the corresponding amine (Table 5). TABLE 5 Hydrogenation ofimines using some [RuXY((VI))₂] or [RuXY(VI)(IV)] Test Sub. ComplexCom/base Conv./time 1 1 [RuCl₂((VI)-1))₂] 240/1200 100/<12 h 2 1[RuCl₂((VI)-2))₂] 2700/13500 100/<4 h 3 1 [RuHCl((VI)-1))₂] 2700/13500100/<4 h 4 1 [RuHCl((VI)-2)₂] 2700/13500 100/<4 h 5 1[RuHCl((IV)-2)((VI)-1))] 1700/8500  100/12 h 6 1[RuHCl((IV)-2)((VI)-2))] 1700/8500  100/12 h 7 1[RuHCl((IV)-1)((VI)-1))] 1000/5000  100/12 h 8 1[RuHCl((IV)-3)((VI)-1))] 1000/5000  100/12 h 9 2 [RuCl₂((VI)-1))₂]1000/5000  100/<8 h 10 2 [RuCl₂((VI)-2))₂] 480/2400 100/<12 h 11 2[RuCl₂((VI)-3))₂] 1100/5500  100/<24 h 12 2 [RuHCl((VI)-1))₂] 380/1900100/<12 h 13 2 [RuHCl((VI)-2))₂] 500/2500 100/<12 h 14 2[RuHCl((IV)-2)((VI)-1))] 1000/5000  100/12 h 15 3 [RuCl₂((VI)-1))₂]*550/2750 100/<12 h 16 3 [RuCl₂((VI)-2))₂]* 550/2750 100/<12 h 17 3[RuHCl((VI)-1))₂]* 550/2750 100/<12 h 18 3 [RuHCl((VI)-2)₂]* 550/2750100/<12 h 19 3 [RuHCl((IV)-2)((VI)-1))]* 1000/5000  100/12 hSub.: Substrate: 1) = N-(phenylmethylene)-benzenamine, 2) =N-(1-phenylethylidene)-benzenamine, 3) =N-(1-phenylethylidene)-benzenemethanamineCom/base: molar ratio in ppm relative to the substrateConv./time = conversion (in %, analysed by NMR) of the imine into thecorresponding amine at the indicated time in hours.Reaction conditions: H₂ gas (≈3.5 atm.), 20° C.*Hydrogenation of the neat substrate

EXAMPLE 6 Catalytic Hydrogenation of an Aldehyde Using [Ru(V)₂XY] or[Ru(VI)₂XY] Prepared in situ i) Preparation of the New Ligands ofFormula (V) or (VI) Used in the Example A.3-(Dicyclohexylphosphino)-1-propylamine ((VI)-4)

10 g (54 mmol) dicyclohexylphosphine, 3.1 g (54 mmol) allylamine and 0.2g ditertiobutylperoxide were stirred under nitrogen in an autoclave for2 hours at 150° C. The resulting mixture was fractionnated by vacuumdistillation to give the desired aminophosphine (colorless liquid) in92% purity and 50% yield.

¹³C-NMR (CDCl₃): 43.6(t, CH₂—NH₂); 33.4-33.3(d, P—CH cyclohexyl);33.4-18.3(t, cyclohexyl) MS (relative intensities): 255(M+, 0.6),172(100), 130(54.7), 131(39.8), 90(35.1).

B. 2-[2-(Diisobutylphosphino)-ethyl pyridine ((V)-1)

10 g (68 mmol) diisobutylphosphine, 7.1 g (68 mmol) 2-vinyl pyridine and0.1 g 2,2′-azobis(isobutyronitrile) (AIBN, VAZO® 64) were stirred undernitrogen in a glass reactor for 2 hours at 85° C. The resulting mixturewas fractionated by vacuum distillation to give the desiredaminophosphine (colourless liquid) in 95% purity and 60% yield.

¹³C-NMR (CDCl₃): 160.4(s, ′C—N Py); 149.3-122.9(d, Py ring); 30.3(t,CH₂-Py); 28.9(t, P—CH₂CH₂-Py); 38.5(t, PCH₂ iBu)

³¹P {¹H} NMR (CDCl₃): 45.66 ppm.

MS (relative intensities): 194(100), 138(47), 136(15.6), 195(13.5).

C. 2-[2-Diisobutylphosphino)-ethyl]-1H-Imidazole ((V)-2)

10 g (68 mmol) diisobutylphosphine, 6.4 g (68 mmol) 1-vinyl imidazoleand 0.1 g 2,2′-azobis(isobutyronitrile) (AIBN, VAZO® 64) were stirredunder nitrogen in a glass reactor for 2 hours at 85° C. The resultingmixture was fractionated by vacuum distillation to give the desiredaminophosphine (colourless liquid) in 96% purity and 50% yield.

¹³C-NMR (CDCl₃): 136.7, 129.5, 118.5(d, Im); 44.8(t, C—N Im); 31.2(t,P—CH₂CH₂-Im) 38.9(t, PCH₂ iBu).

MS (relative intensities): 240(M+,100), 239(89), 128(91), 95(90).

ii) Preparation in situ of a Ru/(ligand) solution from[Ru(COD)(methvlallyl)₂]

The whole procedure described herebelow is carried out under inertatmosphere. 31.9 mg (0.1 mmol) of [Ru(COD)(methylallyl)₂] were dissolvedin 1 ml of CH₂Cl₂, and 0.10 mmol of HBF₄.Et₂O were added to thesolution. The solution thus obtained was stirred at room temperature for2 h, then 0.2 mmol of the desired ligand were added and the resultingmixture stirred for 2 h at room temperature. Finally, to the resultingsolution were added 9 ml of CH₂Cl₂.

iii) Hydrogenation

In a Schlenk tube, in a glove box under inert atmosphere, an appropriatequantity of sodium methoxide, according to Table 6 or 7 (column A), wasdissolved in an appropriate quantity of iso-propanol, according to Table6 or 7 (column B). Then an appropriate quantity of Sandranal, accordingto Table 6 or 7 (column B), was added and the mixture was stirred for 5minutes. To the resulting solution was added an appropriate volume ofthe Ru/(ligand) solution, according to Table 6 or 7 (column C), thelatter being obtained as in here-in-above using the desired ligand.After 10 minutes stirring the solution was transferred into a bombwherein solution was warmed at 40° C. and left under 30 atm. of H₂. Thereaction was followed by GC, and once the starting product hasdisappeared the reaction was cooled to room temperature and the pressurelowered to 1 atm.

The ligand structure, the quantities and results for each test issummarized in Table 6 or 7. TABLE 6 Hydrogenation of Sandranal using aRu complex with ligands of formula (V) Test Complex A B C Com/baseConv./time 1 [RuXY((V)-1))₂]^(a)) 0.3 25.75 1 80/44000 86/16 h 2[RuXY((V)-2))₂]^(a)) 0.3 25.75 1 80/44000 64/16 h

TABLE 7 Hydrogenation of Sandranal using a Ru complex with ligands offormula (VI) Conv./ Test Complex A B C Com/base time 1[RuXY((VI)-4))₂]^(a)) 0.3 25.75 1 80/44000 74/8 h 2[RuXY((VI)-4))₂]^(a)) 0.3 25.75 0.5 40/44000 78/20 h 3[RuXY((VI)-4))₂]^(a)) 0.3 25.75 0.25 20/44000 80/24 h 4[RuXY((VI)-1))₂]^(a)) 0.6 103 0.5 10/22000 95/6 h  5*[RuXY((VI)-5))₂]^(a)) 1.2 103 0.5 10/45000 91/7 h ^(a))X and Y representa hydrogen atom or an alkoxy radical Sandranal:2-ethyl-4-(2′,2′,3′-trimethyl-3′-cyclopenten-1′-yl)-2-buten-1-alCom/base: molar ratio in ppm relative to the substrate Conv./time =conversion (in %, analyzed by GC) of the aldehyde into the correspondingalcohol at the indicated time in hours.

A = grams of NaOMe used in the test B = grams of ^(i)PrOH used in thetest; grams of Sandranal used in the test C = volume (in ml) of theRu/(V) or Ru/(VI) solution used in the test

EXAMPLE 7 Catalytic Hydrogenation of Ketones Using [RuXY((V′))₂]

TABLE 8 Structure of the ligands of formula (V′) used for the synthesisof the corresponding complexes structure name

(V′)-1

(V′)-2

(V′)-3

(V′)-4Ligands (V′)-1 and (V′)-2 are commercially available from STREM.Ligands (V′)-3 and (V′)-4 were obtained from the corresponding amineaccording the method described by Gao et al. in Polyhedron 1996, 15,1241

Preparation of the Complex [RuCl₂((V)-1)₂]

This complex has been obtained by reacting (V′)-1 (562 mg, 1.408 mmole)and [RuCl₂(DMSO)₄] (341 mg, 0.616 mmole) in refluxing toluene (20 ml)under stirring for 8 hour, during which an orange precipitate is formed.After cooling at room temperature, the solid was filtered washed withcold toluene and then with hexane and finally dried under vacuum. 376 mgof [RuCl₂((V′)-1)₂] were obtained (yield 66%).

³¹P{¹H} NMR (CD₂Cl₂): 60.7 ppm (s).

Preparation of the Complex [RuCl₂((V′)-2)₂]

This complex has been obtained by reacting (V′)-2 (255 mg, 0.580 mmole)and [RuCl₂(PPh₃)₃] (270 mg, 0.282 mmole) in toluene (20 ml) during 30min at room temperature. Then the solution was refluxed for 8 hour andnext the resulting red-purple solution cooled at room temperature. Aftera small amount of solid was removed by filtration, then the resultingsolution was concentrated to 5 ml and the product precipitated by adding100 ml of pentane and the suspension stirred for 2 hours. Finally, theprecipitate was collected by filtration, washed with pentane and driedunder vacuum. 300 mg of [RuCl₂((V′)-2)₂] were obtained (yield=100%)

¹H NMR (CD₂Cl₂): Aromatic protons between 6.2 and 9.2 ppm.

³¹P {¹H} NMR (CD₂Cl₂): 49.6 ppm (s).

Preparation of the Complex [RuCl₂((V)-3)₂]

This complex has been obtained by reacting (V′)-3 (190 mg, 0.529 mmole)and [RuCl₂(PPh₃)₃] (221 mg, 0.231 mmole) in CH₂Cl₂ (10 mL) for 18 hoursat room The resulting red solution was concentrated to 1 ml and theproduct was precipitated by adding 50 ml of pentane and stirring for 2hours. Finally, the precipitate was collected by filtration, washed withpentane and dried under vacuum. 160 mg of red orange [RuCl₂((V′)-3)₂]were obtained (yield=78%)

¹³C NMR (CD₂Cl₂): N—CH₂ at 66.7 ppm; N—CH₂—CH₂ at 41.5 ppm; CH(CH₃)₂ at26.8 ppm; CH₃ at 22.5 and 23.1 ppm; N═CH at 168.8 ppm, aromatic protonsbetween 127 and 140 ppm.

³¹P {¹H} NMR (CD₂Cl₂): 52.6 ppm (s).

Preparation of the Complex [RuCl₂((V)-4)₂]

This complex has been obtained by reacting (V′)-4 (225 mg, 0.529 mmole)and [RuCl₂(PPh₃)₃] (230 mg, 0.240 mmole) in CH₂Cl₂ (10 ml) for 3 days atroom temperature. The resulting solution was concentrated to 1 ml, theproduct was precipitated by adding 50 ml of pentane and the suspentionstirred for 2 hours. Finally, the precipitate was collected byfiltration, washed with pentane and dried under vacuum. 140 mg of[RuCl₂((V′)-3)₂] were obtained (yield=60%)

¹H NMR (CD₂Cl₂): Aliphatics protons between e 0.6 and 5.2 ppm, Aromaticprotons between 6.2 and 7.5 ppm, N═CH at 8.15 ppm (AB system).

³C NMR (CD₂Cl₂): Aliphatic carbons between 14 and 76 ppm (20 signals,all of the carbons give two resonances), Aromatic protons between 127and 140 ppm, N═CH at 168.2 and 169.1 ppm.

³¹P {¹H} NMR (CD₂Cl₂): 52.7 ppm (AB system).

Hydrogenation a Substrate to the Corresponding Alcohol

An aliquot of a 2.1 M solution of substrate in ^(i)PrOH, representing 20mmoles of said substrate, the desired amount of ^(t)BuOK were introducedinto an autoclave and stirred until complete dissolution of the base.Afterward, to said solution was added an adequate amount of a stocksolution of the desired complex dissolved in CH₂Cl₂ (typical metalconcentration is 0.02 M). Then, the autoclave was purged 3 times withH₂, and finally warmed at 60° C. under 45 bar of H₂. The reaction wasfollowed by GC, and once the starting product has disappeared thereaction mixture was cooled to room temperature and the pressure loweredto 1 atm. The results are summarized in the Table 9. TABLE 9Hydrogenation of a substrate using some complexes [RuXY((V′))₂] TestSub. Complex Com/base Conv./time 1 1 [RuCl₂((V′)-1)₂] 10/4500 12/24 h 21 [RuCl₂((V′)-1)₂]  10/45000 27/24 h 3 1 [RuCl₂((V′)-2)₂] 10/4500  9/24h 4 1 [RuCl₂((V′)-2)₂]  10/45000 28/24 h 5 2 [RuCl₂((V′)-2)₂] 100/45000 7/24 h 6 2 [RuCl₂((V′)-2)₂]  100/450000 21/24 h 7 1 [RuCl₂((V′)-3)₂]10/4500 45/24 h 8 1 [RuCl₂((V′)-3)₂]  10/45000 100/6 h  9 1[RuCl₂((V′)-4)₂] 10/4500 68/24 h 10 1 [RuCl₂((V′)-4)₂]  10/45000 100/24h Sub. = substrate, 1) = acetophenone, 2) =3,3-dimethyl-5-(2′,2′,3′-trimethyl-3′-cyclopenten-1′-yl)-4-penten-2-one.Com/base: molar ratio in ppm relative to the substrateConv./time = conversion (in %, analyzed by GC) of the substrate into thecorresponding alcohol at the indicated time in hours

EXAMPLE 8 Catalytic Hydrogenation of Acetophenone Using Some[RuXY((VI)-1)₂] Without Addition of a Base

Under an atmosphere of hydrogen gas (40 atm) at 60° C., catalyticamounts of [RuHCl((Vl)-1)₂] described in Example 1, readily catalyzedthe hydrogenation of acetophenone to phenylethanol without the additionof a base. A typical catalytic run for a catalyst/substrate (c/s) ratioof 10 ppm and using [RuHCl((VI)-1)₂] is as follows:

In a Schlenk flask, under Ar and at ambient temperature,[RuHCl((VI)-1)₂] (12 mg, 0.02 mmol), (as obtained in example 1b), wassuspended in i-PrOH (1 ml), and the resulting suspension stirred for ca.5 min. 20 μl (0.0004 mmol) of the finely dispersed light-yellowsuspension of [RuHCl((VI)-1)₂] were added to a solution of acetophenone(4.80 g, 40 mmol) in i-PrOH (14.4 ml) that had been charged into aautoclave under Ar. The autoclave was sealed and pressurised with 40 barof H₂, and its contents stirred and heated to 60° C. Samples foranalysis by GC were periodically withdrawn, and the reaction times andthe results are given in the Table 10. TABLE 10 Hydrogenation ofacetophenone using [RuHCl((VI)-1)₂] without base Test Complex ComConv./time Conv./time 1 [RuHCl((VI)-1)₂] 100 100/10 m 2 [RuHCl((VI)-1)₂]10  70/45 m 100/3 h  3 [RuHCl((VI)-1)₂] 2  93/4 h 4 [RuHCl((VI)-1)₂]*100  8/20 h 5 [Ru(AcO)₂((VI)-1)₂] 100  65/3 h 100/20 h 6[Ru(AcO)₂((VI)-1)₂] 10 100/20 hCom: molar ratio in ppm relative to the substrateConv./time = conversion (in %, analyzed by GC) of the substrate into thecorresponding alcohol at the indicated time in hours (h) or in minute(m)*for comparison, test performed with the same experimental procedure butwithout H₂ gas (reduction by hydrogen transfer)

1. A complex of formula (II):[Ru(L)₁(L′)₁XY]  (II″) wherein: X and Y represent, simultaneously orindependently, a hydrogen or chlorine atom, a methoxy, ethoxy orisopropoxy radical, or a CH₃COO or CH₃CH₂COO radical; L′ represents abidentate P—P ligand of formula

wherein R² and R³ represent a linear, branched or cyclic C₂ to C₆ alkylgroup or an aromatic ring, possibly substituted, and Q represents thebutane-1,4-diyl radical, possibly substituted, a ferrocenediyl or abinaphthyldiyl radical, possibly substituted; the possible substituentsof the Q group are C₁ to C₅ alkoxy or polyalkyleneglycol groups, C₁ toC₄ alkyl groups, or C₅ to C₁₀ cycloalkyl or aromatic groups; and L is aligand of formula (V), (V′), (VI), or (VI′)

wherein: the dotted lines in formula (V′) or (VI′) indicate the presenceof a phenyl or a naphthyl group; G′ represents a R⁶C═NR¹ group or a C═Nfunction-containing heterocycle, possibly substituted and possiblycontaining other heteroatoms; R¹ represents a hydrogen atom or a C₁ toC₄ linear or branched alkyl group, possibly substituted; R² and R³ areas defined above; b represents 1 or 2; R⁶ and R⁷ represent,simultaneously or independently, a hydrogen atom, a linear or branchedC₁ to C₄ alkyl group, possibly substituted, or an aromatic ring possiblysubstituted; or R⁶ and R¹ may optionally be bonded together to form asaturated heterocycle, possibly substituted and possibly containingother heteroatoms; the possible substituents of R¹ to R³, R⁶ and R⁷ areC₁ to C₅ alkoxy or polyalkyleneglycol groups, C₁ to C₄ alkyl groups, C₅to C₁₀ cycloalkyl or aromatic groups.
 2. The complex of formula 1,wherein L is a ligand of formula (V) or (V′)

and R² and R³ represent a linear, branched or cyclic C₂ to C₆ alkylgroup or an aromatic ring, possibly substituted; and R⁶ represents ahydrogen atom, a linear or branched C₁ to C₄ alkyl group, possiblysubstituted, or an aromatic ring, possibly substituted.
 3. The complexof claim 1 wherein L is a ligand of formula (VI), or (VI′)


4. The complex of formula 1, wherein X represents a hydrogen atom and Yrepresents a hydrogen or chlorine atom, a methoxy, ethoxy or isopropoxyradical, or a CH₃COO or CH₃CH₂COO radical.
 5. The complex of formula 1,wherein X and Y represent a hydrogen atom or a CH₃COO or CH₃CH₂COOradical.